2,5-di-substituted 4-oxazolealkanoic acids and esters

ABSTRACT

2,5-Di-substituted 4-oxazolealkanoic acids and esters thereof of the formula: ##STR1## WHEREIN M REPRESENTS AN INTEGER OF 1 TO 2; R 1  represents an alkyl group having 1 to 4 carbon atoms; n represents an integer of 1 to 2; R represents a mono- or di-substituted phenyl group (in which the substituents are selected from the group consisting of a halogen atom, a methyl group, a methoxy group, a nitro group, a trifluoromethyl group, a phenyl group, a halogen-substituted phenyl group, a phenoxy group and a halogen-substituted phenoxy group), a pyridyl group, a halogen-substituted pyridyl group, a furyl group, a halogen-substituted furyl group, a thienyl group, a halogen-substituted thienyl group, a naphthyl group or a halogen-substituted naphthyl group; when m represents an integer of 1, Y represents an hydrogen atom, an alkyl group having 1 to 2 carbon atoms, a benzyl group or a pyridylmethyl group; and when m represents an integer of 2, Y represents a trimethylene group. These compounds are useful as drugs for the treatment of arteriosclerosis, thrombosis and hypertension with lipid metabolism disorder.

This is a division of application Ser. No. 557,692, filed Mar. 12, 1975,now U.S. Pat. No. 4,012,412.

This invention relates to novel and therapeutically valuable compoundsof the formula: ##STR2## WHEREIN M REPRESENTS AN INTEGER OF 1 TO 2; R¹represents an alkyl group having 1 to 4 carbon atoms; n represents aninteger of 1 to 2; R represents a mono- or di-substituted phenyl group(in which the substituents are selected from the group consisting of ahalogen atom, a methyl group, a methoxy group, a nitro group, atrifluoromethyl group, a phenyl group, a halogen-substituted phenylgroup, a phenoxy group and a halogen-substituted phenoxy group), apyridyl group, a halogen-substituted pyridyl group, a furyl group, ahalogen-substituted furyl group, a thienyl group, a halogen-substitutedthienyl group, a naphthyl group or a halogen-substituted naphthyl group;when m represents an integer of 1, Y represents an hydrogen atom, analkyl group having 1 to 2 carbon atoms, a benzyl group or apyridylmethyl group (e.g. 2-pyridylmethyl, 3-pyridylmethyl); and when mrepresents an integer of 2, Y represents a trimethylene group.

The compounds of formula [I] can be produced by one of the followingmethods (a) to (c).

A. In the case of compounds of formula [I] wherein m represents aninteger of 1 and Y represents an alkyl group having 1 to 2 carbon atoms,a benzyl group or a pyridylmethyl group:

i. By dehydrating a compound of the formula: ##STR3## wherein Y¹represents an alkyl group having 1 to 2 carbon atoms, a benzyl group ora pyridylmethyl group and other symbols are as defined above.

The dehydration is carried out by treating the compound of formula [II]with a dehydrating agent (e.g. phosphorus pentoxide, phosphoruspentachloride, thionyl chloride, phosphorus oxychloride, tosyl chloride)in an inert solvent (e.g. benzene, toluene, ligroin, chloroform,1,2-dichloroethane, methylene chloride, carbon tetrachloride),preferably with phosphorus pentoxide in refluxing 1,2-dichloroethane inthe presence of diatomaceous earth or glass beads as promoter ofstirring.

ii. By reacting a compound of the formula: ##STR4## wherein R, R¹ and nare as defined above, or a functional derivative thereof with a compoundof the formula:

    X -- Y.sup.1                                               [IV]

wherein X represents a halogen atom, an alkyl- or aryl-sulfonyloxy group(e.g. p-tolylsulfonyloxy or methylsulfonyloxy) or hydroxy group and Y¹is as defined above.

The functional derivative of the compound of formula [III] is, forexample, acid halide, acid anhydride or mixed acid anhydride.

The reaction is usually carried out in an aprotic polar solvent (e.g.dimethylformamide, dimethylacetamide, dimethylsulfoxide) in the presenceof an organic base (e.g. triethylamine, pyridine), or in a water or amixture of water and water-miscible organic solvent in the presence ofan inorganic base (e.g. sodium hydroxide, sodium carbonate, sodiumbicarbonate), or under heating in an alcohol corresponding to thecompound of formula [IV] in the presence of a catalyst (e.g.hydrochloric, sulfuric acid).

In the case of the reaction of the functional derivative of the compoundof formula [III] with the compound of formula [IV], the reaction isusually carried out in an alcohol corresponding to the compound offormula [IV] in the presence of an organic base (e.g. triethylamine,pyridine) at appropriate temperature depending on the reactivation ofthe starting compounds.

b. In the case of compounds of formula [I] wherein m represents aninteger of 1 and Y represents a hydrogen atom, by hydrolyzing a compoundof the formula: ##STR5## wherein Y¹, R, R¹ and n are as defined above.

The hydrolysis is carried out by treating the compound of formula [V]with an acid or an alkali, preferably with an alkali hydroxide (e.g.NaOH, KOH), in a solvent such as an alcohol (e.g. methanol, ethanol), aketone (e.g. acetone, methyl ethyl ketone), an ether (e.g. dioxane,tetrahydrofuran), water or a mixture thereof at room temperature.

c. In the case of compounds of formula [I] wherein m represents aninteger of 2, by reacting a compound of formula [III] or a functionalderivative thereof with a compound of the formula:

    X -- (CH.sub.2).sub.3 -- X                                 [VI]

wherein X is as defined above.

The reaction is carried out in a manner as described in (ii) above.

The compounds of formula [I] possess excellent pharmacologicalproperties such as hypolipidemic and anti-thrombotic actions, as shown,for example, by the following tests, and are useful as drugs for thetreatment of arteriosclerosis, thrombosis and hypertension with lipidmetabolism disorder.

For example, the compounds of formula [I] listed below have thefollowing pharmacological properties:

A: ethyl 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate

B: 3-pyridylmethyl 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate

C: ethyl 2-(3,4-dichlorophenyl)-5-ethoxy-4-oxazoleacetate

D: 3-[2-(4-pyridyl)-5-ethoxy-4-oxazole]propionic acid

The tests were carried out by the following methods:

Hypolipidemic Action

i. Male rats with normal serum lipid (Table 1)

Table 1 shows the change in serum lipid levels observed after the 5 daysconsecutive administration of the test compound to Wistar strain malerats weighing 150-200 g. Each test group was composed of more than 5rats. The test compound was orally given by a gastric tube. Serumcholesterol and triglyceride levels were measured by the standardmethods using an autoanalyzer (Technicon Inc.). The levels in thecontrol (placebo) group were considered as 100% and the reduction (%) inthe test group was calculated.

ii. Dietary hyperlipidemia in male mice (Table 2)

dd-Strain male mice weighing 20-25 g. were used. Each group was composedof 8 mice. Animals were fed with NMF food (Oriental Yeast Co., Tokyo)containing 1% of cholesterol, 0.2% of cholic acid and 5% of olive oil,and the serum cholesterol level was measured by the use of anautoanalyzer after 5 days administration of the test compound. Thelevels in the test group was compared with that in the control groupgiven the same diet.

iii. Triton hyperlipidemia in male mice (Table 3)

Each group was composed of eight dd-strain male mice weighing 20-25 g.Immediately after intraperitoneal administration of the test compound tothe animals, Triton WR-1339 was intraveniously given. Eighteen hoursafter Triton administration, the serum cholesterol level was measuredand compared with that of the control group treated in the same way.

Anti-thrombotic Action

One hour after oral administration of the test compound to male miceweighing 20-25 g., the tail vein was punctured and the end of bleedingtime was measured in Ringer's solution of 37° C. according to the methoddescribed by Karl Dottl in "Medizin and Chemie," 3, 276 (1936). Thebleeding time induced by platelet thrombi was compared with that of thecontrol group, and the rate of prolongation was calculated as an indexof anti-thrombotic activity. The results are shown in Table 4.

Acute Toxicity

The test compound was orally administered to groups each of 5 male miceand rats respectively. The LD₅₀ was calculated from the lethal rate(50%) within two days after administration of the test compound. Theresults are shown in Table 5.

                  Table 1                                                         ______________________________________                                                              Lowering   Lowering                                                           Rate       Rate                                                               (%) of Serum                                                                             (%) of Serum                                            Dose       Cholesterol                                                                              Triglyceride                                 Compound   (mg/kg/day)                                                                              Level      Level                                        ______________________________________                                        A          100        25         45                                           B          100        22         41                                           Clofibrate 100        31         35                                           (for comparison)                                                              ______________________________________                                    

                  Table 2                                                         ______________________________________                                                   Dose        Lowering Rate (%) of                                   Compound   (mg/kg/day) Serum Cholesterol Level                                ______________________________________                                        A          100         41                                                                50          21                                                     B          100         43                                                     Clofibrate 100         16                                                     (for comparison)                                                                         50          0                                                      ______________________________________                                    

                  Table 3                                                         ______________________________________                                                   Dose        Lowering Rate (%) of                                   Compound   (mg/kg/day) Serum Cholesterol Level                                ______________________________________                                        A          100         32                                                                50          26                                                     C          100         35                                                                25          18                                                     Clofibrate 100         10                                                     (for comparison)                                                              ______________________________________                                    

                  Table 4                                                         ______________________________________                                                   Dose        Prolongation Rate (%)                                  Compound   (mg/kg/day) of the Bleeding Time                                   ______________________________________                                                   100         439                                                    D          50          321                                                               25          209                                                               12.5        107                                                    Acetylsalicylic                                                                          50          268                                                    Acid       25          65                                                     (for comparison)                                                                         12.5        22                                                     Clofibrate 100         38                                                     (for comparison)                                                              ______________________________________                                    

                  Table 5                                                         ______________________________________                                                   LD.sub.50 (mg/kg) per os                                           Compound     Mouse         Rat                                                ______________________________________                                        A            4000          >4000                                              B            >4000         >4000                                              C            2000          >4000                                              D            >2000         >2000                                              Clofibrate   1500          2300                                               (for comparison)                                                              ______________________________________                                    

In view of the tests including those mentioned above, the compounds [I]of the present invention can be administered safely as drugs for thetreatment of arteriosclerosis, thrombosis and hypertension with lipidmetabolism disorder, in the form of a pharmaceutical preparation with asuitable and conventional carrier or adjuvant, administered orally,without harm to the patient.

The oral daily dose of compound A for human adults usually ranges from150 to 600 milligrams.

    ______________________________________                                        Formulation Example                                                           50 mg. Tablets are prepared from the following compositions:                  ______________________________________                                        Compound A          50 mg.                                                    Lactose             90 mg.                                                    Starch              19 mg.                                                    Microcrystalline Cellulose                                                                        15 mg.                                                    Talc                5 mg.                                                     Magnesium Stearate  1 mg.                                                                         180 mg.                                                   ______________________________________                                    

The present invention will be better understood from the followingexamples, which are merely intended to be illustrative and notlimitative of the present invention.

EXAMPLE 1

A suspension of 30 g. of diethyl N-p-chlorobenzoyl-L-aspartate in 120ml. of 1,2-dichloroethane is added with stirring and heating underreflux to a suspension of 26 g. of phosphorus pentoxide and 16 g. ofdiatomaceous earth in 200 ml. of 1,2-dichloroethane. The mixture isheated under reflux with stirring for 30 minutes. The reaction mixtureis cooled and made alkaline with a saturated aqueous sodium bicarbonatesolution, and the diatomaceous earth is filtered off. The filtrate isallowed to seperate into an aqueous layer and an organic layer in aseparatory funnel. The aqueous layer is extracted with a small amount ofethyl acetate. The extract and the organic layer are combined and thecombined solution is washed with water and concentrated. The residue isrecrystallized from hexane to give 17.8 g. of ethyl2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate melting at 80°-82° C.

EXAMPLE 2

A solution of 10.5 g. of diethyl N-p-methoxybenzoyl-L-asparate in 30 ml.of 1,2-dichloroethane is added with stirring and heating under reflux toa suspension of 10 g. of phosphorus pentoxide and 5.4 g. of diatomaceousearth in 55 ml. of 1,2-dichloroethane. The reaction mixture is treatedin an identical manner as described in Example 1 to give 9.4 g. of aconcentrated residue. The residue is recrystallized from hexane to give7.1 g. of ethyl 2-p-methoxyphenyl-5-ethoxy-4-oxazoleacetate as whiteneedles melting at 48°-49° C.

EXAMPLE 3

A solution of 60 g. of diethyl N-3,4-dichlorobenzoyl-L-aspartate in 300ml. of 1,2-dichloroethane is gradually added dropwise with stirring andheating under reflux to a suspension of 90 g. of phosphorus pentoxideand 60 g. of diatomaceous earth in 550 ml. of 1,2-dichloroethane. Afterthe addition, the mixture is heated under reflux with stirring for about1 hour. The reaction mixture is cooled and made alkaline with an aqueoussodium bicarbonate solution cooled with ice added. The diatomaceousearth is filtered off and the filtrate is transferred into a separatoryfunnel. The lower 1,2-dichloroethane layer is dried over sodium sulfateand concentrated in vacuo. The residue is recrystallized from a mixtureof hexane and ethanol to give 31 g. of ethyl2-(3,4-dichlorophenyl)-5-ethoxy-4-oxazoleacetate as white finecrystalline powder melting at 77°-78° C.

EXAMPLE 4

Diethyl N-m-trifluoromethylbenzoyl-L-aspartate (20 g.) is treated with21 g. of phosphorus pentoxide and 11 g. of diatomaceous earth in anidentical manner as described in Example 3. The crude product isrecrystallized from hexane to give 7.5 g. of ethyl2-m-trifluoromethylphenyl-5-ethoxy-4-oxazoleacetate melting at 41°-43°C.

EXAMPLE 5

A solution of 10.4 g. of potassium hydroxide in 100 ml. of 80% methanolis added dropwise with stirring at room temperature to a solution of 50g. of ethyl 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate (produced by theprocedure of Example 1) in 200 ml. of methanol. The mixture is stirredat room temperature for 3 hours, and the methanol is distilled off invacuo. The residue is diluted with water and extracted with ether. Theaqueous layer is cooled with ice and adjusted to pH 3.5 withhydrochloric acid. The resulting crystals are collected by filtration,dried and recrystallized from ethyl acetate to give 31.0 g. of2-p-chlorophenyl-5-ethoxy-4-oxazoleacetic acid as white scales meltingat 144°-146° C.

EXAMPLE 6

A solution of 4.8 g. of potassium hydroxide in 35 ml. of 80% methanol isadded dropwise with stirring at room temperature to a solution of 17.5g. of ethyl 2-p-methoxyphenyl-5-ethoxy-4-oxazoleacetate (produced by theprocedure of Example 2) in 15 ml. of 80% methanol. The reaction mixtureis treated in an identical manner as described in Example 5. The crudeproduct is recrystallized from ethyl acetate to give 11.3 g. of2-p-methoxyphenyl-5-ethoxy-4-oxazoleacetic acid melting at 129°-131° C.

EXAMPLE 7

A solution of 8.5 g. of potassium hydroxide in 90 ml. of 80% methanol isadded dropwise with stirring at room temperature to a solution of 40 g.of ethyl 2-(3,4-dichlorophenyl)-5-ethoxy-4-oxazoleacetate (produced bythe procedure of Example 3) in 400 ml. of methanol. The mixture isstirred at room temperature for a period of from 3 to 4 hours, and themethanol is distilled off in vacuo. The residue is diluted with waterand extracted with ether. The aqueous layer is cooled with ice andadjusted to pH about 3 with dilute sulfuric acid. The precipitatedcrystals are collected by filtration, dried and recrystallized fromethanol to give 25 g. of 2-(3,4-dichlorophenyl)-5-ethoxy-4-oxazoleaceticacid as white crystals melting at 165°-167° C.

EXAMPLE 8

A solution of 15.0 g. of ethyl2-m-trifluoromethylphenyl-5-ethoxy-4-oxazoleacetate (produced by theprocedure of Example 4) in 15 ml. of methanol is treated with a solutionof 2.9 g. of potassium hydroxide in 30 ml. of 80% methanol in anidentical manner as described in Example 7. The crude product isrecrystallized from a mixture of hexane and ethanol to give 4.5 g. of2-m-trifluoromethylphenyl-5-ethoxy-4-oxazoleacetic acid melting at134°-135° C.

EXAMPLE 9

To a solution of 20 g. of 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetic acidin 100 ml. of dimethylformamide are added 60 ml. of triethylamine and 40ml. of ethyl bromide, and the mixture is stirred overnight at roomtemperature. The course of the reaction is followed by thin-layerchromatography. When the starting compounds disappear, 1 liter of wateris added to the reaction mixture, and the mixture is extracted withethyl acetate. The organic layer is washed with water, with dilutehydrochloric acid and further with water, and then dried andconcentrated. The residue is recrystallized from hexane to give 19.0 g.of ethyl 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate melting at 84°-85°C.

EXAMPLE 10

To a solution of 4.0 g. of 2-p-chlorophenyl-5-ethoxy-4-oxazoleaceticacid in 60 ml. of methanol is added 0.1 ml. of concentrated sulfuricacid, and the mixture is heated for about 30 minutes. After cooling,triethylamine is added to the reaction mixture, and the methanol isdistilled off in vacuo. Water and ethyl acetate are added to theresidue, and the mixture is shaken. The organic layer is washed withwater, dried over sodium sulfate and concentrated. The residue isrecrystallized from hexane to give 3.5 g. of methyl2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate melting at 63°-65° C.

EXAMPLE 11

To a solution of 1.0 of 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetic acidin 15 ml. of benzene is added 1.0 ml. of thionyl chloride, and themixture is heated for 2 hours. The benzene is distilled off in vacuo,and the residue is dissolved in 2 ml. of ether. Methanol (4 ml.) isadded with cooling with ice to the solution followed by addition of 1.0ml. of triethylamine, and the mixture is allowed to stand overnight. Thesolvent is distilled off in vacuo. The residue is purified andrecrystallized in a similar manner as Example 10 to give 0.6 g. ofmethyl 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate melting at 63°-65° C.

EXAMPLE 12

To a solution of 6.0 g. of 2-p-chlorophenyl-5-ethoxy-4-oxazoleaceticacid in 15 ml. of dimethylformamide and 6.5 ml. of triethylamine isadded 2.3 g. of 1,3-dibromopropane, and the mixture is stirred at atemperature of from 35° to 40° C. for 13 hours. Water is added to themixture. The precipitated crystals are collected by filtration, driedand recrystallized from a mixture of ethyl acetate and ethanol to give4.5 g. of trimethylene bis(2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate)melting at 129°-131° C.

EXAMPLE 13 to 64

Using the procedures set forth in the above examples, but substitutingequivalent amount of the appropriate starting materials, the followingcompounds are also produced:

    __________________________________________________________________________     ##STR6##                                                                     Example                                                                            R              R.sup.1                                                                           Y     m n Physical Constant                           __________________________________________________________________________    13   o-chlorophenyl ethyl                                                                             ethyl 1 1 n.sub.D.sup.20 = 1.5502                     14   m-chlorophenyl ethyl                                                                             ethyl 1 1 M.P. 44-45° C.                       15   p-chlorophenyl butyl                                                                             ethyl 1 1 n.sub.D.sup.20 = 1.5422                     16   p-chlorophenyl ethyl                                                                             ethyl 1 2 M.P. 48-50° C.                       17   p-chlorophenyl ethyl                                                                             benzyl                                                                              1 1 M.P. 66-68° C.                       18   p-nitrophenyl  ethyl                                                                             ethyl 1 1 M.P. 93-94° C.                       19   4-(p-chlorophenyl)phenyl                                                                     ethyl                                                                             ethyl 1 1 M.P. 88-90° C.                       20   3-fluoro-4-chlorophenyl                                                                      ethyl                                                                             ethyl 1 1 M.P. 71-72° C.                       21   3-methyl-4-chlorophenyl                                                                      ethyl                                                                             ethyl 1 1 M.P. 52-54° C.                       22   2-fluoro-4-chlorophenyl                                                                      ethyl                                                                             ethyl 1 1 M.P. 86-88° C.                       23   2-furyl        ethyl                                                                             ethyl 1 1 n.sub.D.sup.20 = 1.5228                     24   2-thienyl      ethyl                                                                             ethyl 1 1 n.sub.D.sup.20 = 1.5537                     25   5-chloro-2-thienyl                                                                           ethyl                                                                             ethyl 1 1 n.sub.D.sup.20 = 1.5595                     26   β-naphthyl                                                                              ethyl                                                                             ethyl 1 1 M.P. 72-74° C.                       27   4-chloro-1-naphthyl                                                                          ethyl                                                                             ethyl 1 1 M.P. 83-85° C.                       28   p-chlorophenyl ethyl                                                                             3-pyridyl-                                                                    methyl                                                                              1 1 M.P. 85-85° C.                       29   p-chlorophenyl butyl                                                                             3-pyridyl-                                                                    methyl                                                                              1 1 M.P. 65-68° C.                       30   p-chlorophenyl ethyl                                                                             2-pyridyl-                                                                    methyl                                                                              1 1 M.P. 67-68° C.                       31   p-nitrophenyl  ethyl                                                                             2-pyridyl-                                                                    methyl                                                                              1 1 M.P. 101-103° C.                     32   2-furyl        ethyl                                                                             3-pyridyl-                                                                    methyl                                                                              1 1 n.sub.D.sup.20 = 1.5405                     33   5-chloro-2-thienyl                                                                           ethyl                                                                             3-pyridyl-                                                                    methyl                                                                              1 1 M.P. 71-73° C.                       34   4-chloro-1-naphthyl                                                                          ethyl                                                                             3-pyridyl-                                                                    methyl                                                                              1 1 M.P. 98-100° C.                      35   6-chloro-3-pyridyl                                                                           ethyl                                                                             3-pyridyl-                                                                    methyl                                                                              1 1 M.P. 96-97° C.                       36   p-chlorophenyl ethyl                                                                             H     1 2 M.P. 129-131° C.                     37   m-chlorophenyl ethyl                                                                             H     1 1 M.P. 133-134° C.                     38   p-chlorophenyl methyl                                                                            H     1 1 M.P. 120-122° C.                     39   p-chlorophenyl butyl                                                                             H     1 1 M.P. 138-140° C.                     40   p-tolyl        ethyl                                                                             H     1 1 M.P. 119-121° C.                     41   p-nitrophenyl  ethyl                                                                             H     1 1 M.P. 188.5-189.5° C.                 42   4-(p-chlorophenyl)phenyl                                                                     ethyl                                                                             H     1 1 M.P. 141-143° C.                     43   4-(p-chlorophenoxy)phenyl                                                                    ethyl                                                                             H     1 1 M.P. 138-140° C.                     44   2,4-dichlorophenyl                                                                           ethyl                                                                             H     1 1 M.P. 119-120° C.                     45   3-fluoro-4-chlorophenyl                                                                      ethyl                                                                             H     1 1 M.P. 158-160° C.                     46   2-fluoro-4-chlorophenyl                                                                      ethyl                                                                             H     1 1 M.P. 131-133° C.                     47   3-methyl-4-chlorophenyl                                                                      ethyl                                                                             H     1 1 M.P. 141-143° C.                     48   2-furyl        ethyl                                                                             H     1 1 M.P. 109-110° C.                     49   5-bromo-2-furyl                                                                              ethyl                                                                             H     1 1 M.P. 131-132° C.                     50   2-thienyl      ethyl                                                                             H     1 1 M.P. 129-130° C.                     51   5-chloro-2-thienyl                                                                           ethyl                                                                             H     1 1 M.P. 140-141° C.                     52   β-naphthyl                                                                              ethyl                                                                             H     1 1 M.P. 158-160° C.                     53   α-naphthyl                                                                             ethyl                                                                             H     1 1 M.P. 124-126° C.                     54   4-chloro-1-naphthyl                                                                          ethyl                                                                             H     1 1 M.P. 159-160° C.                     55   3-pyridyl      ethyl                                                                             H     1 1 M.P. 166-168° C.                     56   3-pyridyl      ethyl                                                                             H     1 2 M.P. 121-123° C.                     57   4-pyridyl      ethyl                                                                             H     1 2 M.P. 146-147° C.                     58   2-pyridyl      ethyl                                                                             H     1 2 M.P. 143-145° C.                     59   2-pyridyl      ethyl                                                                             H     1 1 M.P. 145-147° C.                     60   4-pyridyl      ethyl                                                                             H     1 1 M.P. 180-181° C.                     61   6-chloro-3-pyridyl                                                                           ethyl                                                                             H     1 1 M.P. 164-165° C.                     62   2-chloro-3-pyridyl                                                                           ethyl                                                                             H     1 2 M.P. 115-117° C.                     63   2-chloro-3-pyridyl                                                                           ethyl                                                                             H     1 1 M.P. 151-153° C.                     64   6-chloro-3-pyridyl                                                                           ethyl                                                                             H     1 2 M.P. 122-124° C.                     __________________________________________________________________________

what is claimed is:
 1. A compound of the formula: ##STR7## wherein R¹represents an alkyl group having 1 to 4 carbon atoms; n represents aninteger of 1 to 2; R represents a mono- or di-substituted phenyl group(in which the substituents are selected from the group consisting of ahalogen atom and a nitro group), a pyridyl group, a halogen-substitutedpyridyl group, a furyl group, a halogen-substituted furyl group, anaphthyl group or a halogen-substituted naphthyl group; and Y representsa hydrogen atom or a pyridylmethyl group, with the proviso that when Ris not pyridyl group or halogen-substituted pyridyl group, Y can only bepyridylmethyl.
 2. A compound of the formula: ##STR8## wherein R¹represents an alkyl group having 2 to 4 carbon atoms; n represents aninteger of 1 to 2; R represents a mono-or di-substituted phenyl group(in which the substituents are selected from the group consisting of ahalogen atom and a nitro group), a pyridyl group, a halogen-substitutedpyridyl group, a furyl group or a halogen-substituted naphthyl group;and Y represents a hydrogen atom or a pyridylmethyl group, with theproviso that when R is not pyridyl group or halogen-substituted pyridylgroup, Y can only be pyridylmethyl.
 3. A compound of the claim1:3-pyridylmethyl 2-p-chlorophenyl-5-ethoxy-4-oxazoleacetate.
 4. Acompound of the claim 1:3-[2-(4-pyridyl)-5-ethoxy-4-oxazole]propionicacid.